In this proposal, we seek to develop a set of new tools to assess and enhance the efficacy of anti-cancer therapies that have immediate clinical relevance. In particular, we have developed and embedded methods for real-time quantitative parametric ultrasound imaging of vascular volume/density and flow rate to assess tumor therapies in a clinical scanner and will evaluate and validate those methods here. Our aims for the assessment of therapeutic efficacy include: evaluate the use of ultrasound methods to estimate flow rate and vascular volume/density in the assessment of therapeutic response;migrate the methods to real-time, on-scanner measurement;and use ultrasound feedback together with histology to optimize treatment with a cocktail of appropriate drugs. Further, we endeavor to enhance therapeutic efficacy by increasing vascular permeability and nanoparticle accumulation using ultrasound. In our initial studies using 2-minute insonation with a low thermal dose, we found that accumulation of liposomes in an insonified tumor increases ~three-fold to as much as 22%ID/g and the accumulation within insonified muscle or lymph nodes increased 3-10 fold. At our site and others the combination of ablative therapies and nanoparticle drug administration has already begun and as MR-guided ultrasound enters the clinic, this combination will be used more frequently. Our aims for the enhancement of efficacy with ultrasound are to: determine the mechanism for ultrasound-enhanced increases in vascular permeability;maximize ultrasound enhancement of the accumulation of particles in a tumor and surrounding tissue;establish a pharmacokinetic model that describes ultrasound-enhanced permeability;and compare the efficacy of particle injection immediately before and after ultrasound and incorporate US- enhanced delivery into a strategy that includes an anti-angiogenic drug, chemotherapeutics an ultrasound monitoring of response. PUBLIC HEALTH RELEVANCE: Currently, one in 4 deaths in the United States is due to cancer. Many new therapeutic strategies can be employed;however, efficient methods to test these strategies are required. We are completing the development of an ultrasound-based strategy for the assessment of therapeutic efficacy that provides quantitative, repeatable and user-independent measures. Further, we are developing methods to enhance therapeutic efficacy using ultrasound by enhancing the accumulation of drug within the tumor.